Identification of Ferroptosis-Related Prognostic Signature and Subtypes Related to the Immune Microenvironment for Breast Cancer Patients Receiving Neoadjuvant Chemotherapy

Abstract

PurposeTo identify molecular clusters associated with ferroptosis and to develop a ferroptosis-related signature for providing novel potential targets for the recurrence-free survival and treatment of breast cancer.MethodsFerroptosis-related gene (FRG) signature was constructed by univariate and multivariate Cox regression and least absolute shrinkage and selection operator (LASSO). Receiver operating characteristic curves, Kaplan–Meier survival analysis, principal component analysis, and univariate and multivariate Cox regression analyses in the training and test cohorts were used to evaluate the application of this signature. Quantitative reverse transcriptase–PCR (qRT-PCR) was employed to detect the expression of FRGs in the model. Furthermore, the correlations between the signature and immune microenvironment, somatic mutation, and chemotherapeutic drugs sensitivity were explored.ResultsInternal and external validations affirmed that relapse-free survival differed significantly between the high-risk and low-risk groups. Univariate and multivariate Cox regression analyses indicated that the riskScore was an independent prognostic factor for BRCA. The areas under the curve (AUCs) for predicting 1-, 2-, and 3-year survival in the training and test cohorts were satisfactory. Significant differences were also found in the immune microenvironment and IC50 of chemotherapeutic drugs between different risk groups. Furthermore, we divided patients into three clusters based on 18 FRGs to ameliorate the situation of immunotherapy failure in BRCA.ConclusionsThe FRG signature functions as a robust prognostic predictor of the immune microenvironment and therapeutic response, with great potential to guide individualized treatment strategies in the future.

ATP6AP1 is a potential prognostic biomarker and is associated with iron metabolism in breast cancer

“…In vivo , iron metabolism and homeostasis are linked with the TME, while ferroptosis plays an important role in tumor immunity ( Lu et al, 2021 ). In a previous study, 18 Ferroptosis-related genes (FRG) were used to divide breast cancer patients into three clusters to improve immunotherapy outcomes, and an immunomicroenvironment and therapeutic response can be prognostically predicted by the FRG signature ( Xu et al, 2022 ). Based on the hallmark gene sets, ATP6AP1 expression was positively associated only with the myogenesis pathway.…”

Revolutionizing breast cancer treatment: Harnessing the related mechanisms and drugs for regulated cell death (Review)

“…Zhang et al (82) constructed a nomogram based on nine ferroptosis-related genes. These ferroptosis-related genes were significantly associated with the level of immune cell infiltration in patients with breast cancer, suggesting their potential use as therapeutic targets or biomarkers (82)(83)(84)(85)(86)(87)(88)(89)(90). Additionally, studies have shown that the deletion of CircRHOT1 inhibits breast cancer cell proliferation and induces apoptosis, while the knockdown of CLCA2, REEP6, SPDEF and CRAT can predict breast cancer prognosis based on metabolic gene classification (91,92).…”